Exoscopic Transoral Supraglottic Laryngectomy.

This article, accompanied by technical notes and video, presents a case of an 85-year-old patient with a cT2N0 laryngeal squamous cell carcinoma treated using CO2 transoral laser exoscopic surgery (TOLES). The procedure achieved en bloc tumor removal with negative margins, preserving laryngeal and swallowing functions, demonstrating TOLES as a viable alternative to traditional microsurgery with enhanced visualization and ergonomics. Laryngoscope, 2024.

Indications, Surgical Strategies And Hearing Outcomes of Revision Stapes Surgery for Otosclerosis: A Systematic Review and Meta-analysis on 2602 Patients.

OBJECTIVE: To summarize current knowledge on the indications, surgical strategies, and auditory outcomes of revision stapes surgery (RSS) for otosclerosis. DATA SOURCES: The search was conducted in PubMed, Scopus, and Web of Science online databases, including papers published since 2000. REVIEW METHODS: The study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We considered original series describing RSS for otosclerosis, reporting postoperative hearing outcomes according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines for conductive hearing loss (CHL) for at least 30 consecutive cases. The quality of included studies was assessed with the Joanna Briggs Institute checklist. Pooled proportion and odds ratio (OR) meta-analysis were conducted using random effect models. RESULTS: Nineteen studies were included, for a total of 2602 patients (2735 ears) and 2359 postoperative hearing results. RSS was mostly performed for recurrent CHL with air-bone gap (ABG)>20 dB. Multiple concomitant causes were often present, with prosthesis placement defect and incus necrosis as the most common causes. The pooled proportion of postoperative ABG<10 dB and ABG<20 dB was 57.2% (95% confidence interval [CI]: 52.8%-61.4%) and 79% (95% CI: 76.0%-81.8%), respectively. Dead ears were 1.2% (95% CI: 0.7%-2.1%). Compared to primary surgery, RSS had a significantly lower rate of ABG<10 dB (OR = 0.36, 95% CI: 0.24%-0.54%; P < .001). Both revision incudostapedotomy with/without incus reconstruction and malleovestibulopexy are viable options with nonsignificant differences in ABG closure rates (P = .182). CONCLUSION: RSS is challenging and requires the surgeon to carefully evaluate all potential causes of previous failure and tailor the intervention according to intraoperative findings. In most cases, ABG closure within 20 dB can be achieved with a relatively low risk of dead ears.

The prognostic role of salivary miRNAs in oral squamous cell carcinoma: technical challenges and clinical perspectives.

In management of oral squamous cell carcinoma (OSCC), only a few biomarkers, ranging from clinical and histopathological features to molecular alterations, have been demonstrated to have clinical and prognostic utility. The intent of this narrative review is to present current findings on the use of salivary microRNAs (miRNAs) as prognostic oncologic biomarkers in patients with OSCC. The ability to predict survival or recurrence during follow-up by quantification of specific miRNAs in saliva has been shown in a number of studies, and serves as a possible feature to address in future well-designed clinical studies to confirm their prognostic value. The non-invasiveness of liquid biopsy techniques, the ease of saliva collection, and the abundance and stability of miRNAs in such a biologic fluid make it an attractive combination to improve management of OSCC. For salivary miRNAs to be used in routine practice, however, methodological and sampling standardisation are still needed to increase the power and accuracy of the results obtained.

Lateral hypopharyngectomy with laryngeal preservation reconstructed with inlay fascio-cutaneous free flaps: clinical and functional outcomes.

Objective: Lateral hypopharyngectomy (LH) is one of the organ-preservation surgical strategies available for treatment of selected naïve early squamous cell carcinoma (SCC), as well as for rarer non-SCC tumours and persistent/recurrent/second primaries after chemoradiation of the lateral wall of the piriform sinus. Its reconstructive methods have been the subject of different approaches without a general consensus. The aim of the present study is to describe a retrospective series of LH reconstructed by inlay fascio-cutaneous free flaps, reporting on oncological and functional outcomes. Methods: Patients who underwent LH at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia, Italy, between 2017 and 2023 were retrospectively reviewed. Clinical history, tumour histotype, postoperative complications, functional, and oncological outcomes were collected. Results: Seven patients (6 males, 1 female) were included. In all, 29% had a naïve neoplasm, while 71% had recurrent disease. The final histology included 3 SCC, 2 synovial sarcomas, one liposarcoma, and one single-site mucosal metastasis from cutaneous melanoma. Negative margins were achieved in 6 patients (86%). All patients had swallowing rehabilitation by speech therapists and were able to safely eat a free diet at discharge, except for one who needed a percutaneous endoscopic gastrostomy to support nutritional oral intake. After a mean follow-up of 34.3 months, all patients except one are alive. Conclusions: Our study showed that, in selected cases, it is possible to radically remove lateral hypopharyngeal tumours with laryngeal preservation and free flaps inlay reconstruction, with a low rate of complications and acceptable functional and oncological results.

Epistaxis and Clinic Blood Pressure Values: Is There a Relationship?

INTRODUCTION: Epistaxis is the most common otorhinolaryngological emergency and historically there have been an important debate whether there is a cause-effect relationship with high blood pressure. AIM: This retrospective study explored whether hypertension is a significant risk factor for epistaxis in Emergency Department (ED) patients and examined associations between blood pressure levels and epistaxis episodes. MATERIALS AND METHODS: Two groups were studied: Group A (patients with epistaxis) and Group B (control). Patient characteristics, comorbidities, and medication use were recorded. Blood pressure measurements were taken upon ED arrival and after specialist evaluation. Statistical analyses included descriptive statistics, T-test, χ2 test, and logistic regression. RESULTS: Group A, enrolled from April 2014 to February 2015, included 102 patients, mean age 67, male-female ratio 2:1. Blood pressure on arrival was over 140/90 mmHg in 73%, decreasing to 26% after 30 minutes. Group B, enrolled from May 2023 to August 2023, included 126 patients, mean age 59, male-female ratio 2:1. Blood pressure on arrival was over 140/90 mmHg in 60%, decreasing to 23% after 30 minutes. Both groups showed reduced blood pressure post-evaluation. Logistic regression identified anticoagulant and/or antiplatelet therapy as the main independent risk factor for epistaxis. Age, sex, blood pressure levels, and hypertension did not significantly influence epistaxis occurrence. CONCLUSION: No significant correlation between hypertension and epistaxis was found. Anticoagulant and/or antiplatelet therapy was the primary independent risk factor, highlighting the importance of considering medication history in evaluating epistaxis.

The prognostic role of MRI-based radiomics in tongue carcinoma: a multicentric validation study.

PURPOSE: Radiomics is an emerging field that utilizes quantitative features extracted from medical images to predict clinically meaningful outcomes. Validating findings is crucial to assess radiomics applicability. We aimed to validate previously published magnetic resonance imaging (MRI) radiomics models to predict oncological outcomes in oral tongue squamous cell carcinoma (OTSCC). MATERIALS AND METHODS: Retrospective multicentric study on OTSCC surgically treated from 2010 to 2019. All patients performed preoperative MRI, including contrast-enhanced T1-weighted (CE-T1), diffusion-weighted sequences and apparent diffusion coefficient map. We evaluated overall survival (OS), locoregional recurrence-free survival (LRRFS), cause-specific mortality (CSM). We elaborated different models based on clinical and radiomic data. C-indexes assessed the prediction accuracy of the models. RESULTS: We collected 112 consecutive independent patients from three Italian Institutions to validate the previously published MRI radiomic models based on 79 different patients. The C-indexes for the hybrid clinical-radiomic models in the validation cohort were lower than those in the training cohort but remained > 0.5 in most cases. CE-T1 sequence provided the best fit to the models: the C-indexes obtained were 0.61, 0.59, 0.64 (pretreatment model) and 0.65, 0.69, 0.70 (posttreatment model) for OS, LRRFS and CSM, respectively. CONCLUSION: Our clinical-radiomic models retain a potential to predict OS, LRRFS and CSM in heterogeneous cohorts across different centers. These findings encourage further research, aimed at overcoming current limitations, due to the variability of imaging acquisition, processing and tumor volume delineation.

Morbidity of multimodal treatments including endoscopic surgery for sinonasal malignancies: Results of an international collaborative study on 940 patients (MUSES).

INTRODUCTION: In the management of sinonasal malignancies treatment-induced morbidity and mortality is gaining relevance both for surgical approaches (endoscopic and open resection) and non-surgical therapies. The aim of this multicenter study is to assess complications associated with endoscopic surgery and non-surgical treatments (neoadjuvant and/or adjuvant) for malignant sinonasal tumors. METHODS: All patients with nasoethmoidal malignancies treated with curative intent with endoscopic or endoscopic-assisted surgery at three referral centers with uniform management policies were included. Neo- and/or adjuvant (chemo)radiotherapy was administered according to histology and pathological report. Demographics, treatment characteristics, and complications related both to the surgical and non-surgical approaches were retrieved. The data were analyzed with univariate and multivariate statistics to assess independent predictors of complications. RESULTS: Nine hundred and forty patients were included, 643 males (68%) and 297 females (32%). A total of 225 complications were identified in 187 patients (19.9%): cerebrospinal fluid (CSF) leak (3.5%), mucocele (2.3%), surgical site bleeding (2.0%), epiphora (2.0%), and radionecrosis (2.0%) were the most common. Treatment-related mortality was 0.4%. Variables independently associated with complications at multivariate analysis were principally dural resection (OR 1.92), cranioendoscopic or multiportal resection (OR 2.93), dural repair with multilayer technique with less than three layers (OR 2.17), and graft different from iliotibial tract (OR 3.29). CONCLUSION: Our study shows that modern endoscopic treatments and radiotherapy for sinonasal malignancies are associated with limited morbidity and treatment-related mortality. CSF leak and radionecrosis, although rare, remain the most frequent complications and should be further addressed by future research efforts.

Is precision medicine the solution to improve organ preservation in laryngeal/hypopharyngeal cancer? A position paper by the Preserve Research Group.

In locally advanced (LA) laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC), larynx preservation (LP) strategies aim at the cure of the disease while preserving a functional larynx, thus avoiding total laryngectomy and the associated impact on the quality of life. In the last decades, apart from transoral and open-neck organ preservation approaches, several non-surgical regimens have been investigated: radiotherapy alone, alternate, concurrent or sequential chemoradiation, and bioradiotherapy. Despite major progress, the identification of reliable and effective predictors for treatment response remains a clinical challenge. This review examines the current state of LP in LA-LHSCC and the need for predictive factors, highlighting the importance of the PRESERVE trial in addressing this gap. The PRESERVE trial represents a pivotal initiative aimed at finding the optimal therapy for laryngeal preservation specific to each patient through a retrospective analysis of data from previous LP trials and prospectively validating findings. The goal of the PRESERVE trial is to develop a comprehensive predictive classifier that integrates clinical, molecular, and multi-omics data, thereby enhancing the precision and efficacy of patient selection for LP protocols.

Artificial intelligence for automatic detection and segmentation of nasal polyposis: a pilot study.

PURPOSE: Accurate diagnosis and quantification of polyps and symptoms are pivotal for planning the therapeutic strategy of Chronic rhinosinusitis with nasal polyposis (CRSwNP). This pilot study aimed to develop an artificial intelligence (AI)-based image analysis system capable of segmenting nasal polyps from nasal endoscopy videos. METHODS: Recorded nasal videoendoscopies from 52 patients diagnosed with CRSwNP between 2019 and 2022 were retrospectively analyzed. Images extracted were manually segmented on the web application Roboflow. A dataset of 342 images was generated and divided into training (80%), validation (10%), and testing (10%) sets. The Ultralytics YOLOv8.0.28 model was employed for automated segmentation. RESULTS: The YOLOv8s-seg model consisted of 195 layers and required 42.4 GFLOPs for operation. When tested against the validation set, the algorithm achieved a precision of 0.91, recall of 0.839, and mean average precision at 50% IoU (mAP50) of 0.949. For the segmentation task, similar metrics were observed, including a mAP ranging from 0.675 to 0.679 for IoUs between 50% and 95%. CONCLUSIONS: The study shows that a carefully trained AI algorithm can effectively identify and delineate nasal polyps in patients with CRSwNP. Despite certain limitations like the focus on CRSwNP-specific samples, the algorithm presents a promising complementary tool to existing diagnostic methods.

Computer Vision Foundation Models in Endoscopy: Proof of Concept in Oropharyngeal Cancer.

OBJECTIVES: To evaluate the performance of vision transformer-derived image embeddings for distinguishing between normal and neoplastic tissues in the oropharynx and to investigate the potential of computer vision (CV) foundation models in medical imaging. METHODS: Computational study using endoscopic frames with a focus on the application of a self-supervised vision transformer model (DINOv2) for tissue classification. High-definition endoscopic images were used to extract image patches that were then normalized and processed using the DINOv2 model to obtain embeddings. These embeddings served as input for a standard support vector machine (SVM) to classify the tissues as neoplastic or normal. The model's discriminative performance was validated using an 80-20 train-validation split. RESULTS: From 38 endoscopic NBI videos, 327 image patches were analyzed. The classification results in the validation cohort demonstrated high accuracy (92%) and precision (89%), with a perfect recall (100%) and an F1-score of 94%. The receiver operating characteristic (ROC) curve yielded an area under the curve (AUC) of 0.96. CONCLUSION: The use of large vision model-derived embeddings effectively differentiated between neoplastic and normal oropharyngeal tissues. This study supports the feasibility of employing CV foundation models like DINOv2 in the endoscopic evaluation of mucosal lesions, potentially augmenting diagnostic precision in Otorhinolaryngology. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Magnetic Resonance Imaging after Nasopharyngeal Endoscopic Resection and Skull Base Reconstruction.

Background: Postoperative imaging after nasopharyngeal endoscopic resection (NER) and skull base reconstruction is quite challenging due to the complexity of the post-surgical and regional anatomy. Methods: In this retrospective observational study, we included patients treated with NER from 2009 to 2019 and submitted to Magnetic Resonance Imaging (MRI) 6 and 12 months after surgery. A radiologist with 15 years of experience analyzed all MRI scans. Results: A total of 50 patients were considered in this study, 18 of whom were excluded due to imaging unavailability, and 16 of whom were not considered due to major complications and/or persistent disease. Sixteen patients were evaluated to identify the expected findings. Inflammatory changes were observed in 16/64 subsites, and regression of these changes was observed in 8/64 at 1 year. Fibrosis was observed in 5/64 subsites and was unmodified at 1 year. The nasoseptal flap showed homogeneous enhancement at 6 months (100%) and at 1 year. The temporo-parietal fascia flap (TPFF) showed a decrease in the T2- signal intensity of the mucosal layer in 57% of the patients at 1 year and a decrease in enhancement in 43%. Conclusions: Identifying the expected findings after NER and skull base reconstruction has a pivotal role in the identification of complications and recurrence.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Transoral laser exoscopic surgery of the larynx: state of the art and comparison with traditional transoral laser microsurgery.

Objective: To evaluate the efficacy of transoral laser exoscopic surgery (TOLES) in a unicentric series of patients affected by benign and malignant glottic and supraglottic lesions, and compare outcomes with those of transoral laser microsurgery (TOLMS). Methods: To demonstrate the non-inferiority of TOLES in terms of operative time, margin status and complication rates, we compared outcomes of 93 patients treated by TOLES between July 2021 and July 2023 with those of a match-paired group of 107 historical patients treated by TOLMS. To perform a multiparametric ergonomic evaluation of TOLES vs TOLMS, we used observational methods for biomechanical overload risk assessment and wearable technologies comparing 15 procedures with TOLES vs a paired match of 13 surgeries performed with TOLMS by the same surgeon. Results: No significant differences were found in terms of surgical duration, positive margins, or complications between TOLES and TOLMS. Ergonomics assessment by inertial measurement units and electromyographic surface electrodes demonstrated a reduced biomechanical overload with TOLES compared to TOLMS. Conclusions: The many advantages of TOLES, such as its superior didactic value, better digital control of light even through small-bored laryngoscopes, improved binocular vision, and increase in surgical performance by 3 or 4-hand techniques, are difficult to be quantified. In contrast, its non-inferiority in terms of oncological results and better ergonomics compared to TOLMS are demonstrated herein.

Recurrent Laryngeal Nerve Intraoperative Neuromonitoring Indications in Non-Thyroid and Non-Parathyroid Surgery.

Introperative nerve monitoring (IONM) of the recurrent laryngeal nerve (RLN) is a well-established technique to aid in thyroid/parathyroid surgery. However, there is little evidence to support its use in non-thyroid or non-parathyroid surgery. The aim of this paper was to review the current evidence regarding the use of IONM in non-thyroid/non-parathyroid surgery in the head and neck and thorax. A literature search was performed from their inception up to January 2024, including the term "recurrent laryngeal nerve monitoring". IONM in non-thyroid/non-parathyroid surgery has mainly been previously described in oesophageal surgery and in tracheal resections. However, there is little published evidence on the role of IONM with other resections in the vicinity of the RLN. Current evidence is low-level for the use of RLN IONM in non-thyroid/non-parathyroid surgery. However, clinicians should consider its use in surgery for pathologies where the RLN is exposed and could be injured.

Initial surgical management of sporadic medullary thyroid cancer: Guidelines based optimal care - A systematic review.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old. CONCLUSION: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

Assessment of the risk of malignancy in Bethesda III thyroid nodules: a comprehensive review.

The increasing prevalence of thyroid cancer emphasizes the need for a thorough assessment of risk of malignancy in Bethesda III nodules. Various methods ranging commercial platforms of molecular genetic testing (including Afirma® GEC, Afirma® GSC, ThyroSeq® V3, RosettaGX®, ThyGeNEXT®/ThyraMIR®, ThyroidPRINT®) to radionuclide scans and ultrasonography have been investigated to provide a more nuanced comprehension of risk estimation. The integration of molecular studies and imaging techniques into clinical practice may provide clinicians with improved and personalized risk assessment. This integrated approach we feel may enable clinicians to carefully tailor interventions, thereby minimizing the likelihood of unnecessary thyroid surgeries and overall crafting the optimal treatment. By aligning with the evolving landscape of personalized healthcare, this comprehensive strategy ensures a patient-centric approach to thyroid nodule and thyroid cancer management.

Measuring financial toxicity in head and neck cancer: a systematic review.

Objective: The current study systematically reviews the literature about financial toxicity (FT) in head and neck cancer patients. Three databases were reviewed: PubMed, Scopus and Web of Science. Methods: Full text English papers published from 2000 to 2022 reporting on quantitative results about FT in head and neck cancer survivors collected through structured questionnaires or interviews were included. Results: Twenty-seven articles were included. Most of the articles were published after 2015 and from United States. There was a slight prevalence of papers dealing with oropharyngeal cancer, squamous-cell carcinoma and locally advanced head and neck cancer. Measures of FT were obtained through validated questionnaires like COST, FIT and FDQ. Collected data were mostly referrable to financial spending, financial resources, psychosocial aspect, support seeking, coping care and coping lifestyle subdomain. FT scores by COST were found to be worse in the COVID era. Financial counseling and adequate information about the costs of treatment were two effective strategies to mitigate FT. Conclusions: FT is a relatively new challenge in head and neck cancer treatment, whose expenses are higher than therapies for other cancers. A universal method to assess FT and a unified guideline for the administration of questionnaires are needed to mitigate FT and to improve patient outcomes.

Evaluation of DNA methylation levels of SEPT9 and SHOX2 in plasma of patients with head and neck squamous cell carcinoma using droplet digital PCR.

Head and neck squamous cell carcinoma (HNSCC) is the seventh most commonly diagnosed cancer globally. HNSCC develops from the mucosa of the oral cavity, pharynx and larynx. Methylation levels of septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) genes in circulating cell­free DNA (ccfDNA) are considered epigenetic biomarkers and have shown predictive value in preliminary reports in HNSCC. Liquid biopsy is a non­invasive procedure that collects tumor­derived molecules, including ccfDNA. In the present study, a droplet digital PCR (ddPCR)­based assay was developed to detect DNA methylation levels of circulating SEPT9 and SHOX2 in the plasma of patients with HNSCC. The assay was first set up using commercial methylated and unmethylated DNA. The dynamic changes in the methylation levels of SEPT9 and SHOX2 were then quantified in 20 patients with HNSCC during follow­up. The results highlighted: i) The ability of the ddPCR­based assay to detect very low copies of methylated molecules; ii) the significant decrease in SEPT9 and SHOX2 methylation levels in the plasma of patients with HNSCC at the first time points of follow­up with respect to T0; iii) a different trend of longitudinally DNA methylation variations in small groups of stratified patients. The absolute and precise quantification of SEPT9 and SHOX2 methylation levels in HNSCC may be useful for studies with translational potential.

Thyroid cartilage infiltration in advanced laryngeal cancer: prognostic implications and predictive modelling.

Objective: Detection of laryngeal cartilage invasion is of great importance in staging of laryngeal squamous cell carcinoma (LSCC). The role of prognosticators in locally advanced laryngeal cancer are still widely debated. This study aimed to assess the impact of volume of thyroid cartilage infiltration, as well as other histopathologic variables, on patient survival. Materials and methods: We retrospectively analysed 74 patients affected by pT4 LSCC and treated with total laryngectomy between 2005 and 2021 at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia, Italy. We considered as potential prognosticators histological grade, perineural (PNI) and lympho-vascular invasion (LVI), thyroid cartilage infiltration, and pTN staging. Pre-operative CT or MRI were analysed to quantify the volume of cartilage infiltration using 3D Slicer software. Results: The 1-, 3-, and 5-year disease free survivals (DFS) were 76%, 66%, and 64%, respectively. Using machine learning models, we found that the volume of thyroid cartilage infiltration had high correlation with DFS. Patients with a higher volume (>670 mm3) of infiltration had a worse prognosis compared to those with a lower volume. Conclusions: Our study confirms the essential role of LVI as prognosticator in advanced LSCC and, more innovatively, highlights the volume of thyroid cartilage infiltration as another promising prognostic factor.